This invention is directed to the use of the compound 6-amino-1-(2-deoxy-.alpha.-D-erythro-pentofuranosyl)imidazo[4,5-C]-pyridin -4-one as an immunoenhancing agent, an immunoadjuvant agent, an immunopotentiating agent and as a immunorestorative agent especially for human T cells.
Certain C8 substituted guanosine derivatives have been reported to display immunostimulatory activity. These derivatives, 8-bromoguanosine, 8-mercaptoguanosine and 7-methyl-8-oxoguanosine, have demonstrated the ability to stimulate proliferation of B cells, see Goodman, M. G. and W. O. Weigle, "Activation of lymphocytes by a thiol-derivatized nucleoside: characterization of cellular parameters and responsive subpopulations", J. Immunol., 130:551, 1983; Goodman, M. G. and W. O. Weigle, "Intracellular lymphocytes activation and carrier-mediated transport of C8-substituted ribonucleosides", Proc. Natl. Acad Sci. USA, 81:862, 1984; and Goodman, M. G. and W. O. Weigle, "Induction of immunoglobulin secretion by a simple nucleoside derivative", J. Immunol., 128:2399, 1982. This effect is exerted predominantly upon a subset of mature B lymphocytes and to a lesser degree on a subset of immature B cell.
In addition these C8 substituted guanosine nucleosides have also been shown to be capable of (a) augmenting polyclonal activation of B cells to secrete immunoglobulins in both murine and human systems, (b) increasing thymus dependent and thymus independent antibody immune responses and (c) transmitting T cell like inductive signals to B cells, see Goodman, M. G. and W. O. Weigle, "T cell-replacing activity of C8-derivatized guanine ribonucleosides", J. Immunol., 130:2042, 1983; Goodman, M. G. and W. O. Weigle, "Manifold amplification of in vitro immunity in normal and immunodeficient mice by ribonucleosides derivatized at C8 of guanine", Proc. Natl. Acad. Sci. USA, 80:3452, 1983; and Goodman, M. G. and W. O. Weigle, "Derivatized guanosine nucleosides: a new class of adjuvant for in vitro antibody responses", J. Immunol., 130:2580, 1983. Recently, 8-bromoguanosine was also shown to activate macrophages and NK cells. This group of compounds is further described in U.S. Pat. Nos. 4,539,205, 4,643,992 and 4,746,651.
Another group of low molecular weight compounds, certain pyrimidinones, have also been reported to increase the level of polyclonal and antigen-specific antibody production, see Skulnick, H. I., S. D. Weed, E. E. Edison, H. E. Renis, W. Wierenga, and D. A. Stringfellow, "Prymidinones 12-Amino-5-halo-6-aryl-4(3H)-pyrimidinones interferon-inducing antiviral agent", J. Med. Chem., 28:1864, 1984; Fast, P.E. D. A. Hattfield, and D. A. Stringfellow, "Polyclonal B cell activation and stimulation of specific antibody responses by 5-Halo-pyrimidones with antiviral and antineoplastic activity", J. Biol. Reso. Modif., 1:199, 1982; and Lotzova, E., C. A. Savary, and D. A. Stringfellow, "5-Halo-6-phenylpyrimidinones: new molecules with cancer therapeutic potential and interferon inducing capacity are strong inducer of murine natural killer cells", J. Immunol., 139:965, 1983. In addition, these pyrimidinones were found to enhance interferon release and NK cell activity and induced cytotoxic macrophages.
Both of these C8 substituted guanosines and pyrimidinones however were unable to activate T cells.
T lymphocytes are involved in the generation of effector cytotoxic antibody, and cytotoxic and immunoregulatory T cells. They mediate regulation of cellular and humoral responses by interacting target populations either via direct cell to cell contact or by secretion of a cascade of lymphokines and suppressor factors that provide proliferative, differentiation and immunosuppressive signals.
Cytotoxic T lymphocytes have been shown to play an important role in defense against viruses and neoplasms. Adoptive transfer of H-2 restricted cytotoxic T lymphocytes with high degree specificity was recently shown to protect T cell deficient mice with influenza pneumonia. Similarly, mice, or rats with established tumors were cured or their lives were prolonged following transfer of specific cytotoxic T lymphocytes expanded in vitro with interleukin-2. It has also been reported (see Sharma, B. and S. Gupta, "Antigen-specific primary cytotoxic T lymphocyte response in acquired immune deficiency syndrome (AIDS) and AIDS related complex", Clin. Exp. Immunol., 62: 296, 1985) that interleukin-2 could restore depressed cytotoxic T cell function in some AIDS patients and patients with AIDS related complex.
Intrinsic or acquired abnormality in any of these T cells or their functions can lead to the development of cancer, viral and other infections, immunodeficiency disorders and autoimmune diseases.
The synthesis and limited in vitro antiviral activity of the compound 6-amino-(2-deoxy-.alpha.-D-erythro-pentofuranosyl)imidazo[4,5,-C]pyridin-4 -one is reported in Revankar, G. R., P. K. Gupta, A. D. Adams, N. K. Dalley, P. A. McKernan, P. D. Cook, P. G. Canonico, and R. K. Robins, "Synthesis and Antiviral/antitumor activities of certain 3-Deazaguanine nucleosides and nucleotides", J. Med. Chem., 27:1389, 1984. Further in this report the compound 6-amino-(2-deoxy-.alpha.-D-erythro-pentofuranosyl)-imidazo[4,5,-C]pyridin- 4-one is noted as being devoid of any useful antitumor activity.